Skip to main content
NCBI home page
Molecular Pathology : MP logoLink to Molecular Pathology : MP
. 1999 Aug;52(4):169–173. doi: 10.1136/mp.52.4.169

The adenomatous polyposis coli protein.

I S Näthke 1
PMCID: PMC395695  PMID: 10694935

Abstract

Mutations in the adenomatous polyposis coli (APC) gene are associated with most colorectal cancers. The APC protein has been implicated in many aspects of tumour development. This article will discuss recent data suggesting that APC may have multiple functions in the cell. First, APC is a component of the Wnt signalling pathway; second, APC may have a role in cell migration; finally, APC may regulate proliferation and apoptosis.

Full Text

The Full Text of this article is available as a PDF (131.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aberle H., Bauer A., Stappert J., Kispert A., Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997 Jul 1;16(13):3797–3804. doi: 10.1093/emboj/16.13.3797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmed Y., Hayashi S., Levine A., Wieschaus E. Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development. Cell. 1998 Jun 26;93(7):1171–1182. doi: 10.1016/s0092-8674(00)81461-0. [DOI] [PubMed] [Google Scholar]
  3. Baeg G. H., Matsumine A., Kuroda T., Bhattacharjee R. N., Miyashiro I., Toyoshima K., Akiyama T. The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. EMBO J. 1995 Nov 15;14(22):5618–5625. doi: 10.1002/j.1460-2075.1995.tb00249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barth A. I., Pollack A. L., Altschuler Y., Mostov K. E., Nelson W. J. NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion. J Cell Biol. 1997 Feb 10;136(3):693–706. doi: 10.1083/jcb.136.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Behrens J., Jerchow B. A., Würtele M., Grimm J., Asbrand C., Wirtz R., Kühl M., Wedlich D., Birchmeier W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998 Apr 24;280(5363):596–599. doi: 10.1126/science.280.5363.596. [DOI] [PubMed] [Google Scholar]
  6. Behrens J., von Kries J. P., Kühl M., Bruhn L., Wedlich D., Grosschedl R., Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996 Aug 15;382(6592):638–642. doi: 10.1038/382638a0. [DOI] [PubMed] [Google Scholar]
  7. Ben-Ze'ev A., Geiger B. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol. 1998 Oct;10(5):629–639. doi: 10.1016/s0955-0674(98)80039-2. [DOI] [PubMed] [Google Scholar]
  8. Berrueta L., Kraeft S. K., Tirnauer J. S., Schuyler S. C., Chen L. B., Hill D. E., Pellman D., Bierer B. E. The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10596–10601. doi: 10.1073/pnas.95.18.10596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bhat R. V., Baraban J. M., Johnson R. C., Eipper B. A., Mains R. E. High levels of expression of the tumor suppressor gene APC during development of the rat central nervous system. J Neurosci. 1994 May;14(5 Pt 2):3059–3071. doi: 10.1523/JNEUROSCI.14-05-03059.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chiu C. H., McEntee M. F., Whelan J. Sulindac causes rapid regression of preexisting tumors in Min/+ mice independent of prostaglandin biosynthesis. Cancer Res. 1997 Oct 1;57(19):4267–4273. [PubMed] [Google Scholar]
  11. Deka J., Kuhlmann J., Müller O. A domain within the tumor suppressor protein APC shows very similar biochemical properties as the microtubule-associated protein tau. Eur J Biochem. 1998 May 1;253(3):591–597. doi: 10.1046/j.1432-1327.1998.2530591.x. [DOI] [PubMed] [Google Scholar]
  12. Dierick H., Bejsovec A. Cellular mechanisms of wingless/Wnt signal transduction. Curr Top Dev Biol. 1999;43:153–190. doi: 10.1016/s0070-2153(08)60381-6. [DOI] [PubMed] [Google Scholar]
  13. Dobashi Y., Bhattacharjee R. N., Toyoshima K., Akiyama T. Upregulation of the APC gene product during neuronal differentiation of rat pheochromocytoma PC12 cells. Biochem Biophys Res Commun. 1996 Jul 16;224(2):479–483. doi: 10.1006/bbrc.1996.1052. [DOI] [PubMed] [Google Scholar]
  14. Funayama N., Fagotto F., McCrea P., Gumbiner B. M. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol. 1995 Mar;128(5):959–968. doi: 10.1083/jcb.128.5.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. doi: 10.1016/0092-8674(81)90021-0. [DOI] [PubMed] [Google Scholar]
  16. Hamilton S. R., Liu B., Parsons R. E., Papadopoulos N., Jen J., Powell S. M., Krush A. J., Berk T., Cohen Z., Tetu B. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839–847. doi: 10.1056/NEJM199503303321302. [DOI] [PubMed] [Google Scholar]
  17. Hart M. J., de los Santos R., Albert I. N., Rubinfeld B., Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998 May 7;8(10):573–581. doi: 10.1016/s0960-9822(98)70226-x. [DOI] [PubMed] [Google Scholar]
  18. Hayashi S., Rubinfeld B., Souza B., Polakis P., Wieschaus E., Levine A. J. A Drosophila homolog of the tumor suppressor gene adenomatous polyposis coli down-regulates beta-catenin but its zygotic expression is not essential for the regulation of Armadillo. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):242–247. doi: 10.1073/pnas.94.1.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hermiston M. L., Wong M. H., Gordon J. I. Forced expression of E-cadherin in the mouse intestinal epithelium slows cell migration and provides evidence for nonautonomous regulation of cell fate in a self-renewing system. Genes Dev. 1996 Apr 15;10(8):985–996. doi: 10.1101/gad.10.8.985. [DOI] [PubMed] [Google Scholar]
  20. Hsu S. C., Galceran J., Grosschedl R. Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin. Mol Cell Biol. 1998 Aug;18(8):4807–4818. doi: 10.1128/mcb.18.8.4807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Huber O., Korn R., McLaughlin J., Ohsugi M., Herrmann B. G., Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev. 1996 Sep;59(1):3–10. doi: 10.1016/0925-4773(96)00597-7. [DOI] [PubMed] [Google Scholar]
  22. Ikeda S., Kishida S., Yamamoto H., Murai H., Koyama S., Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998 Mar 2;17(5):1371–1384. doi: 10.1093/emboj/17.5.1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Itoh K., Krupnik V. E., Sokol S. Y. Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and beta-catenin. Curr Biol. 1998 May 7;8(10):591–594. doi: 10.1016/s0960-9822(98)70229-5. [DOI] [PubMed] [Google Scholar]
  24. Kim S. H., Roth K. A., Moser A. R., Gordon J. I. Transgenic mouse models that explore the multistep hypothesis of intestinal neoplasia. J Cell Biol. 1993 Nov;123(4):877–893. doi: 10.1083/jcb.123.4.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. doi: 10.1016/s0092-8674(00)81333-1. [DOI] [PubMed] [Google Scholar]
  26. Korinek V., Barker N., Moerer P., van Donselaar E., Huls G., Peters P. J., Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998 Aug;19(4):379–383. doi: 10.1038/1270. [DOI] [PubMed] [Google Scholar]
  27. Levy D. B., Smith K. J., Beazer-Barclay Y., Hamilton S. R., Vogelstein B., Kinzler K. W. Inactivation of both APC alleles in human and mouse tumors. Cancer Res. 1994 Nov 15;54(22):5953–5958. [PubMed] [Google Scholar]
  28. Luongo C., Moser A. R., Gledhill S., Dove W. F. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res. 1994 Nov 15;54(22):5947–5952. [PubMed] [Google Scholar]
  29. Mahmoud N. N., Boolbol S. K., Bilinski R. T., Martucci C., Chadburn A., Bertagnolli M. M. Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration. Cancer Res. 1997 Nov 15;57(22):5045–5050. [PubMed] [Google Scholar]
  30. Mahmoud N. N., Boolbol S. K., Dannenberg A. J., Mestre J. R., Bilinski R. T., Martucci C., Newmark H. L., Chadburn A., Bertagnolli M. M. The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis. Carcinogenesis. 1998 Jan;19(1):87–91. doi: 10.1093/carcin/19.1.87. [DOI] [PubMed] [Google Scholar]
  31. Marikawa Y., Elinson R. P. beta-TrCP is a negative regulator of Wnt/beta-catenin signaling pathway and dorsal axis formation in Xenopus embryos. Mech Dev. 1998 Sep;77(1):75–80. doi: 10.1016/s0925-4773(98)00134-8. [DOI] [PubMed] [Google Scholar]
  32. Molenaar M., van de Wetering M., Oosterwegel M., Peterson-Maduro J., Godsave S., Korinek V., Roose J., Destrée O., Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell. 1996 Aug 9;86(3):391–399. doi: 10.1016/s0092-8674(00)80112-9. [DOI] [PubMed] [Google Scholar]
  33. Morin P. J., Vogelstein B., Kinzler K. W. Apoptosis and APC in colorectal tumorigenesis. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7950–7954. doi: 10.1073/pnas.93.15.7950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Morrison E. E., Askham J. M., Clissold P., Markham A. F., Meredith D. M. The cellular distribution of the adenomatous polyposis coli tumour suppressor protein in neuroblastoma cells is regulated by microtubule dynamics. Neuroscience. 1997 Nov;81(2):553–563. doi: 10.1016/s0306-4522(97)00099-7. [DOI] [PubMed] [Google Scholar]
  35. Morrison E. E., Askham J., Clissold P., Markham A. F., Meredith D. M. Expression of beta-catenin and the adenomatous polyposis coli tumour suppressor protein in mouse neocortical cells in vitro. Neurosci Lett. 1997 Oct 17;235(3):129–132. doi: 10.1016/s0304-3940(97)00739-8. [DOI] [PubMed] [Google Scholar]
  36. Moser A. R., Dove W. F., Roth K. A., Gordon J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol. 1992 Mar;116(6):1517–1526. doi: 10.1083/jcb.116.6.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Muhua L., Adames N. R., Murphy M. D., Shields C. R., Cooper J. A. A cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein. Nature. 1998 Jun 4;393(6684):487–491. doi: 10.1038/31014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Munemitsu S., Albert I., Souza B., Rubinfeld B., Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3046–3050. doi: 10.1073/pnas.92.7.3046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Munemitsu S., Souza B., Müller O., Albert I., Rubinfeld B., Polakis P. The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res. 1994 Jul 15;54(14):3676–3681. [PubMed] [Google Scholar]
  40. Nakamura T., Hamada F., Ishidate T., Anai K., Kawahara K., Toyoshima K., Akiyama T. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells. 1998 Jun;3(6):395–403. doi: 10.1046/j.1365-2443.1998.00198.x. [DOI] [PubMed] [Google Scholar]
  41. Näthke I. S., Adams C. L., Polakis P., Sellin J. H., Nelson W. J. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol. 1996 Jul;134(1):165–179. doi: 10.1083/jcb.134.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Oshima H., Oshima M., Kobayashi M., Tsutsumi M., Taketo M. M. Morphological and molecular processes of polyp formation in Apc(delta716) knockout mice. Cancer Res. 1997 May 1;57(9):1644–1649. [PubMed] [Google Scholar]
  43. Papkoff J., Rubinfeld B., Schryver B., Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol. 1996 May;16(5):2128–2134. doi: 10.1128/mcb.16.5.2128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Polakis P. Mutations in the APC gene and their implications for protein structure and function. Curr Opin Genet Dev. 1995 Feb;5(1):66–71. doi: 10.1016/s0959-437x(95)90055-1. [DOI] [PubMed] [Google Scholar]
  45. Pollack A. L., Barth A. I., Altschuler Y., Nelson W. J., Mostov K. E. Dynamics of beta-catenin interactions with APC protein regulate epithelial tubulogenesis. J Cell Biol. 1997 Jun 30;137(7):1651–1662. doi: 10.1083/jcb.137.7.1651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Porfiri E., Rubinfeld B., Albert I., Hovanes K., Waterman M., Polakis P. Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene. 1997 Dec 4;15(23):2833–2839. doi: 10.1038/sj.onc.1201462. [DOI] [PubMed] [Google Scholar]
  47. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  48. Rubinfeld B., Souza B., Albert I., Müller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. doi: 10.1126/science.8259518. [DOI] [PubMed] [Google Scholar]
  49. Sakanaka C., Weiss J. B., Williams L. T. Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3020–3023. doi: 10.1073/pnas.95.6.3020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Siegfried E., Perrimon N. Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays. 1994 Jun;16(6):395–404. doi: 10.1002/bies.950160607. [DOI] [PubMed] [Google Scholar]
  51. Smith K. J., Levy D. B., Maupin P., Pollard T. D., Vogelstein B., Kinzler K. W. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 1994 Jul 15;54(14):3672–3675. [PubMed] [Google Scholar]
  52. Stewart D. B., Nelson W. J. Identification of four distinct pools of catenins in mammalian cells and transformation-dependent changes in catenin distributions among these pools. J Biol Chem. 1997 Nov 21;272(47):29652–29662. doi: 10.1074/jbc.272.47.29652. [DOI] [PubMed] [Google Scholar]
  53. Su L. K., Burrell M., Hill D. E., Gyuris J., Brent R., Wiltshire R., Trent J., Vogelstein B., Kinzler K. W. APC binds to the novel protein EB1. Cancer Res. 1995 Jul 15;55(14):2972–2977. [PubMed] [Google Scholar]
  54. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. doi: 10.1126/science.8259519. [DOI] [PubMed] [Google Scholar]
  55. Tanaka E., Sabry J. Making the connection: cytoskeletal rearrangements during growth cone guidance. Cell. 1995 Oct 20;83(2):171–176. doi: 10.1016/0092-8674(95)90158-2. [DOI] [PubMed] [Google Scholar]
  56. Trzepacz C., Lowy A. M., Kordich J. J., Groden J. Phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) by the cyclin-dependent kinase p34. J Biol Chem. 1997 Aug 29;272(35):21681–21684. doi: 10.1074/jbc.272.35.21681. [DOI] [PubMed] [Google Scholar]
  57. Vleminckx K., Wong E., Guger K., Rubinfeld B., Polakis P., Gumbiner B. M. Adenomatous polyposis coli tumor suppressor protein has signaling activity in Xenopus laevis embryos resulting in the induction of an ectopic dorsoanterior axis. J Cell Biol. 1997 Jan 27;136(2):411–420. doi: 10.1083/jcb.136.2.411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wong M. H., Hermiston M. L., Syder A. J., Gordon J. I. Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9588–9593. doi: 10.1073/pnas.93.18.9588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wong M. H., Rubinfeld B., Gordon J. I. Effects of forced expression of an NH2-terminal truncated beta-Catenin on mouse intestinal epithelial homeostasis. J Cell Biol. 1998 May 4;141(3):765–777. doi: 10.1083/jcb.141.3.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yamamoto H., Kishida S., Kishida M., Ikeda S., Takada S., Kikuchi A. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem. 1999 Apr 16;274(16):10681–10684. doi: 10.1074/jbc.274.16.10681. [DOI] [PubMed] [Google Scholar]
  61. Yamamoto H., Kishida S., Uochi T., Ikeda S., Koyama S., Asashima M., Kikuchi A. Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Mol Cell Biol. 1998 May;18(5):2867–2875. doi: 10.1128/mcb.18.5.2867. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular Pathology are provided here courtesy of BMJ Publishing Group

RESOURCES